Hemophilias A and B are due to mutations in the factor VIII and IX genes, respectively. These diseases are good models for gene therapy because of the relatively straightforward clinical parameters that include measurement of the transgene product by simple blood measurements and changes in clotting based on plasma levels. Patients with less than 1% clotting activity have very severe disease, between 1 to 5% a more moderate disease, and 5 to 20% mild disease. A wide-range of circulating factor is well tolerated making gene regulation unnecessary for gene therapy approaches. The liver is the organ in which these two clotting factors are normally synthesized. This makes it an attractive target for gene therapy approaches. While factor IX may be treatable with muscle delivery of a factor IX cDNA, factor VIII produced in the muscle is not efficiently secreted in the bloodstream. Moreover, there are still a number of issues that are unresolved when the muscle and liver approaches for treating FIX deficiency are directly compared. These include the relative risks of inhibitor formation, the ability to reach therapeutic versus curative levels of factor, and the relative dose of vector required to achieve a given level of plasma factor concentration. Recombinant AAV- mediated liver gene transfer has proven to be safe as well as efficacious in both small and large animal models of hemophilia. The goal of the proposal is to develop two phase I rAAV-mediated liver-based clinical trials for the treatment of hemophilias A and B. Our primary goal will be address the safety of this approach in humans. The secondary goal will be demonstrated phenotypic improvement in patients with hemophilia. The trial design here will also provide useful information for future liver- based clinical trials.